Motexafin-Gadolinium Taken Up In vitro by at Least 90% of Glioblastoma Cell Nuclei

Abstract

Purpose: We present preclinical data showing the in vitro intranuclear uptake of motexafin gadolinium by glioblastoma multiforme cells, which could serve as a prelude to the future development of radiosensitizing techniques, such as gadolinium synchrotron stereotactic radiotherapy (GdSSR), a new putative treatment for glioblastoma multiforme. Experimental Design: In this approach, administration of a tumor-seeking Gd-containing compound would be followed by stereotactic external beam radiotherapy with 51-keV photons from a synchrotron source. At least two criteria must be satisfied before this therapy can be established: Gd must accumulate in cancer cells and spare the normal tissue; Gd must be present in almost all the cancer cell nuclei. We address the in vitro intranuclear uptake of motexafin gadolinium in this article.We analyzed the Gd distribution with subcellular resolution in four human glioblastoma cell lines, using three independent methods: two novel synchrotron spectromicroscopic techniques and one confocal microscopy.We present in vitro evidence that the majority of the cell nuclei take up motexafin gadolinium, a drug that is known to selectively reach glioblastoma multiforme. Results: With all three methods, we found Gd in at least 90% of the cell nuclei. The results are highly reproducible across different cell lines. The present data provide evidence for further studies, with the goal of developing GdSSR, a process that will require further in vivo animal and future clinical studies.

Effect of Gd‐DTPA‐BMA on choline signals of HT29 tumors detected by in vivo 1H MRS

“…[4] as being that required to produce the changes observed in our choline T 2 data, and this was found to be in the range of 0.02-0.04 mmol/L. These are lower concentrations than those found by Stasio et al (34) in their long time-period accumulation experiments and were less than or equal to our estimates determined from changes in the water T 2 . Although the Gd-DTPA-BMA concentration estimated from the change in water T 2 values doubled with twice the i.v.…”

“…De Stasio et al (32)(33)(34) demonstrated that Gd-DTPA penetrates both the plasma and nuclear membranes of human glioblastoma cells when they are cultured in 10 mg/mL Gd-DTPA for long periods, eventually reaching concentrations of 600 g/mL, or around 4 mmol/L. They also showed a preferential accumulation of Gd in the cell nuclei (33,34). These reports suggest that the uptake of Gd-DTPA-BMA into tumor cells might be sufficient to affect the relaxation of intracellular cholines.…”

Shifts in oxidation states of cerium oxide nanoparticles detected inside intact hydrated cells and organelles

“…STXM [50] enables high resolution (10–50 nm) imaging and speciation analysis in dried or hydrated cells [61,62,64], as well as the quantification of oxidation states of particles in biofilms or non-biological media [63,65,66]. The minimal damage to biological systems caused by STXM allows subsequent imaging of the cells using other methods.…”

Motexafin gadolinium: a novel radiosensitizer for brain tumors

“…De Stasio and colleagues analyzed the intranuclear distribution of gadolinium in four human GBM cell lines after exposure to motexafin gadolinium. The results were reproduced and corroborated using three different microscopy techniques: x-ray photoelectron emission spectromicroscopy, scanning transmission x-ray microscopy, and confocal fluorescence microscopy [49]. The experiments demonstrated gadolinium in more than 90% of the GBM cell nuclei in vitro after exposure to motexafin gadolinium, and that the concentration of gadolinium increases with duration of exposure to motexafin gadolinium.…”